Eosinophilic esophagitis (EE) is an emerging, and fast-growing disorder characterized by high levels of eosinophils in the esophagus, as well as basal zone hyperplasia. EE is thought to be provoked, in at least a subset of patients, by food allergies or airborne allergen exposure (Rothenberg M E. Eosinophilic gastrointestinal disorders. J Allergy Clin Immunol. 2004; 113:11-28; Fogg M J, Ruchelli E, Spergel J M. Pollen and eosinophilic esophagitis J Allergy Clin Immunol 2003; 112:796-7; refs 1-5). In parallel with other atopic disorders, the incidence of EE appears to be increasing (Noel R J, Putnam P E, Rothenberg M E. Eosinophilic esophagitis. N Eng J Med 2004; 351:940-1; Straumaun A, Simon H U. Eosinophilic esophagitis: escalating epidemiology? J Allergy Clin Immunol 2005; 115:418-9.). The disorder may present with reflux-like symptoms, pain and dysphagia. Symptoms of EE include, for example, abdominal pain, chest pain, choking, difficulty swallowing, failure to thrive, nausea, reflux not relieved by standard anti-flux therapy, skin rash or hives, vomiting, and weight loss. In one series, 15% of EE patients had concurrent developmental delay (Garrett J K, Jameson S C, Thomson B, Collins M H, Wagoner L E, Freese, D K, et al. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol. 2004; 113:115-9.). Diagnosis is often made in young children and depends on the finding of 20 or more to 24 or more eosinophils per high power field (eos/hpf) within esophageal mucosal biopsies. (refs 6-12).
Although EE is becoming more frequently diagnosed throughout developing countries (7, 8, 13-16) many aspects of the disease remain unclear including its etiology, natural history and optimal therapy. Symptoms of EE often mimic those of GER and include vomiting, dysphagia, pain and food impaction (8, 14, 17-20). However, treatment of EE and GERD differ and it is important to distinguish between them, particularly as untreated EE may be associated with esophageal narrowing in 10-30% of cases (14, 18, 20, 21).
Long term systemic steroid therapy can result in significant secondary side effects on growth and bone development, therefore topical steroid formulations are often used to treat EE and potentially other inflammatory gastrointestinal diseases and conditions involving the esophagus. Although treatment with anti-IL-5 monoclonal antibody has been reported to be successful in EE, this therapy is currently not approved for use in children (Guajardo J R, Plotnick L M, Fende J M, Collins M H, Putnam P E, Rothenberg M E. Eosinophil-associated gastrointestinal disorders: a world-wide web based registry. J Pediatr. 2002; 141:576-81.).
Current treatments include elimination diets (22, 23), and elemental formulas (2, 24). Identifying true inciting food allergens can be difficult and elemental formulas are often unpalatable, thereby making dietary interventions complicated (1, 22). Systemic corticosteroids and swallowed topical steroids, such as fluticasone propionate (Flovent™) administered through metered-dose inhaler (MDI), have been shown to induce and maintain low esophageal eosinophil levels (25-30). In one method, for example, a fluticasone metered dose inhaler (MDI) is puffed into the oropharynx and swallowed (Teitelbaum, J E, Fox, V L, Twarog F J, Nurko S, Ntonioli D, Gleich G, Badizadegan K, Furuta G T. Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate. Gastroenterology. 2002; 122:1216-25.). This puff and swallow technique is often difficult for patients, especially smaller children, and especially children with developmental delays, to perform efficiently. This results in a less than effective dose of the topical steroid being delivered to the esophagus.
Systemic corticosteroids are also used to treat inflammatory bowel diseases that are manifested in the esophagus, including, for example, Crohn's disease or allergic gastroenteritis. These drugs are also used to treat inflammatory esophageal conditions other than EE, such as, for example, esophageal inflammation secondary to caustic/irritant ingestion, persistent/recurrent esophageal strictures of any cause and including caustic/irritant ingestion, pill-induced esophagitis (caused when a pill becomes lodged in the esophagus during swallowing, followed by inflammation that persists after the pill is removed), systemic diseases, congenital diseases, or post-surgery inflammation. It is often difficult to deliver an effective dose of corticosteroid to the targeted area of the esophagus. Other inflammatory bowel diseases in which steroid therapy is useful include, for example, Crohn's disease, which may affect any part of the gastrointestinal tract, from the mouth to the anus.
Budesonide, 16,17-(butylidenebis(oxy))-11,21-dihydroxy-, (11-β,16-α)-pregna-1,4-diene-3,20-dione, is a corticosteroid sometimes used in inhaled form to treat inflammatory diseases or conditions such as asthma, or nasal inflammation, or in other forms, such as by oral delivery or enema, to treat other lower inflammatory lower gastrointestinal diseases or conditions such as Crohn's disease.
There is a need for novel methods for preventing and alleviating inflammatory diseases and conditions involving the esophagus. A liquid, long-acting topical corticosteroid preparation is needed.